Abstract
Objective
To evaluate the efficacy and safety of darbepoetin alfa dosed every-other-week (Q2W) to treat anemia in subjects with chronic kidney disease (CKD), not receiving dialysis, who were naïve to erythropoiesis-stimulating agent (ESA) therapy.
Research design and methods
This was an open-label, multicenter, single-arm study enrolling ESA-naïve CKD subjects with baseline hemoglobin (Hb) < 11.0 g/dL. Q2W darbepoetin alfa treatment was initiated at a dose of 0.75 µg/kg and titrated to achieve and maintain Hb levels at 11.0–13.0 g/dL. Treatment was administered from week 1 to week 19.
Main outcome measures
The primary endpoint was the proportion of subjects who achieved Hb ≥ 11 g/dL at any study visit, except in week 1. Hb levels, darbepoetin alfa dose, and safety were also assessed.
Results
Of the 128 subjects who received at least one dose of darbepoetin alfa and of the subjects who completed the study, 118 (92%) and 112 (97%), respectively, achieved a Hb ≥ 11 g/dL in a median time of 5 weeks. Median darbepoetin alfa dose at week 1 and at the time of achieving a Hb ≥ 11 g/dL were 60 and 80 µg, respectively. Darbepoetin alfa was well-tolerated, and short-term adverse events were consistent with those expected in CKD subjects.
Conclusions
This study demonstrates that de novo Q2W darbepoetin alfa was effective in correcting and maintaining Hb levels in ESA-naïve subjects with CKD who were not receiving dialysis. Study limitations, including lack of a control arm for the study and multiple race information for subjects, must be considered in interpreting the results.
Keywords: Anemia, Chronic kidney disease, Darbepoetin alfa, Erythropoietin, Extended dosing
Introduction
Chronic kidney disease (CKD) is often associated with anemia. Anemia develops secondary to CKD as the diseased kidneys lose their ability to produce erythropoietin, which is required to stimulate the bone marrow to produce mature red blood cells1. The decline in hemoglobin (Hb) level may start early in CKD, and progresses as renal function and erythropoietin production decline2,3. Anemia associated with CKD is a risk factor for impaired physical capacity and reduced quality of life, and may contribute to the increased morbidity and mortality seen in CKD4–11.
Guidelines are in place for the treatment of anemia in patients with CKD. The current National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) guidelines for managing CKD-related anemia with erythropoiesis-stimulating agents (ESAs) recommend a Hb target in the range of 11.0–12.0 g/dL. The recent update also includes a guideline that the target Hb should not exceed 13.0 g/dL12. Recent studies have questioned the benefits of treating to high Hb levels13,14, however, evidence supporting improved patient outcomes with ESA therapy, when used according to the label, is clearly documented15–22. ESAs, therefore, provide a means to effectively treat anemia in CKD patients.
Darbepoetin alfa (Aranesp*) is an ESA approved for the treatment of anemia in chronic kidney failure. In the US, the initiation dosing frequency approved by the Food and Drug Administration is weekly (QW) or every other week (Q2W) when patients are naïve to previous ESA therapy. Data from clinical studies have shown that appropriate target Hb levels can be achieved and/or maintained when darbepoetin alfa is administered Q2W23–25. The purpose of the current study was to add to the safety and efficacy data on de novo Q2W administration of subcutaneous (SC) darbepoetin alfa in achieving and maintaining target Hb levels in patients with CKD who were not receiving dialysis.
Patients and methods
Study subjects
Subjects were eligible for inclusion in the study if they were ≥ 18 years of age with a diagnosis of CKD, but not receiving or scheduled to receive dialysis. They were required to have an estimated glomerular filtration rate (eGFR) ≥ 15 mL/min/1.73m2 and ≤ 60 mL/min/1.73m2, using the Modification of Diet in Renal Disease (MDRD) equation26,27; mean Hb level < 11.0 g/dL, based on two screening visits at least 3 days apart; normal serum vitamin B12 and folate levels; and transferrin saturation (TSAT) levels ≥ 15.0%. Subjects were excluded from the study if they had received ESA therapy within 12 weeks before enrollment or received, or were scheduled to receive, a kidney transplant. Additionally, subjects with uncontrolled hypertension (diastolic blood pressure > 110 mmHg or systolic blood pressure > 180 mmHg during screening), cardiovascular disease (acute myocardial infarction or hospitalization for chronic heart failure within 12 weeks before enrollment), and intact parathyroid hormone level > 1500 pg/mL were not enrolled. Subjects who had undergone major surgery within 12 weeks before enrollment (excluding vascular access surgery), had systemic infection or hematologic disease, and/or had received red blood cell (RBC) transfusions within 8 weeks before enrollment were also excluded from the study.
Study design and intervention
This was a 21-week, open-label, multicenter, single-arm study conducted in the United States. The study consisted of an initial 2-week screening period followed by Q2W darbepoetin alfa treatment from week 1 to week 19. The study design is shown in Figure 1.
Figure 1.
Study design
Darbepoetin alfa treatment was initiated at 0.75 µg/kg, rounded to the nearest unit dose (20, 30, 40, 50, 60, 80, 100, 150, 200, or 300 µg). The starting dose was based on the recommended dose in the US label for darbepoetin alfa (0.45 µg/kg administered QW). However, rather than doubling the dose (i.e., 0.90 µg/kg) for Q2W administration, a more conservative approach was chosen when initiating treatment for subjects in this study. Following treatment initiation, darbepoetin alfa doses were adjusted to achieve and maintain target Hb levels in the range of 11.0 to 13.0 g/dL, inclusive, which was a range similar to previously reported ESA trials24,25 and was consistent with clinical practice at the time the study was designed.
Darbepoetin alfa dose adjustments were based on the Hb rate of rise and the most recent Hb measurement. The dose was reduced to the next lower unit dose if the Hb rate of rise in a 2-week period exceeded 1.0 g/dL. If Hb level was < 11.0 g/dL, the dose was increased to the next higher dose. If Hb was > 13.0 g/dL and ≤ 14.0 g/dL, the dose was decreased to the next lower dose. If Hb was > 14.0 g/dL, dosing was withheld until Hb decreased to < 13.0 g/dL and then resumed at the next lower dose. Dose adjustments were permitted no more frequently than every 4 weeks.
Oral and intravenous (IV) iron therapies were encouraged according to clinic policy to ensure that subjects were iron replete (TSAT ≥ 19.5%). If a subject entered the study with TSAT ≥ 15% and < 19.5%, IV or oral iron therapy was recommended to correct TSAT to ≥ 19.5%.
Hb level, vital signs, adverse events (AEs), and concomitant medications were evaluated at baseline, at the time of each administration of darbepoetin alfa, and at the end-of-study visit (week 21). The doses of darbepoetin alfa were recorded at the time of each administration. Hematology (other than Hb level), serum chemistry, and TSAT were assessed at baseline, week 7, and the end-of-study visit (week 21 or early termination). All clinical laboratory assessments were performed at a central laboratory (ICON Laboratories Inc, Farmingdale, New York, USA). Antierythropoietin antibody bioassays (MDS Pharma Services, Saint-Laurent [Montreal], Quebec, Canada) were performed before the start of darbepoetin alfa therapy and at the end-of-study visit.
The study was conducted in accordance with applicable United States Food and Drug Administration and International Conference on Harmonization Good Clinical Practice regulations/guidelines. All subjects gave written informed consent and the study was approved by institutional review boards at participating centers. The study is registered on ClinicalTrials.gov under the registry number NCT00112008.
Endpoints
The primary efficacy endpoint was the proportion of subjects achieving a Hb ≥ 11 g/dL. Secondary endpoints were Hb levels and darbepoetin alfa dose over the duration of the study. Safety endpoints included the frequency and relationship to treatment of AEs, and changes in laboratory parameters and blood pressure.
Statistical analysis
A target sample size of 100 was determined based on having a half-width of 8% for the two-sided 95% confidence interval (CI) of the proportion of subjects achieving a Hb ≥ 11.0 g/dL, assuming that an estimated 80% of subjects would achieve a Hb ≥ 11.0 g/dL. Efficacy analyses were performed on efficacy analysis set, which is defined as subjects who received at least one dose of darbepoetin alfa and had a baseline Hb < 11.0 g/dL. The proportion of subjects who achieved a Hb ≥ 11 g/dL was calculated as the number of subjects who had received at least one dose of darbepoetin alfa, had a baseline Hb < 11.0 g/dL, and had achieved a Hb ≥ 11.0 g/dL, divided by the total number of subjects in efficacy analysis set. A similar proportion was calculated for subjects who completed the study. Safety analyses were performed on subjects who received at least one dose of darbepoetin alfa. Safety analyses included the incidence of AEs tabulated according to system organ class. Only AEs occurring with a ≥ 5% frequency are reported here. Exploratory analysis was also done for subjects with Hb > 13 g/dL and > 14 g/dL at any time during the study. SAS version 8.2 (SAS Institute Inc, Cary, NC, USA) was used for statistical analysis.
Descriptive statistics included mean, standard deviation (SD), and quartiles (25th [Q1] and 75th [Q3] percentiles) for continuous variables, and count and percent for categorical variables. Two-sided 95% CIs were calculated for the primary endpoint. Hodges–Lehmann’s distribution-free 95% CIs28 were calculated for median darbepoetin alfa doses.
Results
Subject characteristics
A total of 128 subjects recruited from 36 centers across the United States were enrolled in the study and included in the efficacy and safety analyses (first subject was enrolled May 2004 and last subject completed the study November 2004). All (100%) subjects received at least one dose of darbepoetin alfa, 117 (91%) completed all planned darbepoetin alfa treatments, and 115 (90%) completed all study assessments (Table 1). Thirteen subjects discontinued participation in the study; of these, 11 subjects discontinued participation during the treatment period and 2 subjects completed treatment but discontinued during the follow-up period. Reasons for discontinuation from the study were AEs other then death (n = 3; one subject due to hyperglycemia, one subject due to cerebrovascular accident, and one subject due to hypertension), death (n = 3), initiation of dialysis (n = 3), noncompliance (n = 2), lost to follow-up (n = 1), or other reasons (n = 1).
Table 1.
Subject disposition
| Darbepoetin alfa n (%) |
|
|---|---|
| Subjects enrolled | 128 |
| Subjects who received darbepoetin alfa | 128 (100) |
| Subjects who completed darbepoetin alfa treatment | 117 (91) |
| Subjects who completed study | 115 (90) |
| Subjects who discontinued study | 13 (10) |
| AEs | 3 (2) |
| Death | 3 (2) |
| Initiation of dialysis | 3 (2) |
| Noncompliance | 2 (2) |
| Lost to follow-up | 1 (1) |
| Other | 1 (1) |
Subject demographics and baseline characteristics are shown in Table 2. The majority of subjects were female (57%) and white (59%). Mean (SD) age was 66.8 (13.7) years. Mean (SD) eGFR, Hb, and TSAT levels were 32.1 (12.2) mL/min/1.73m2, 10.0 (0.6) g/dL, and 23.6% (6.4%), respectively. The mean (SD) time since the onset of CKD was 29.2 (40.1) months. The most common cause of CKD was diabetes mellitus (52%), followed by hypertension (29%). At study entry, 98%, 73%, 38%, and 16% of subjects had histories of hypertension, diabetes, coronary artery disease, and myocardial infarction, respectively.
Table 2.
Subject demographics and baseline characteristics
| N = 128 | |
|---|---|
| Sex, n (%) | |
| Female | 73 (57) |
| Male | 55 (43) |
| Race, n (%) | |
| White or Caucasian | 75 (59) |
| Black or African-American | 40 (31) |
| Hispanic or Latino | 10 (8) |
| Asian | 3 (2) |
| Age (years) | |
| Mean (SD) | 66.8 (13.7) |
| Weight (kg) | |
| n | 127 |
| Mean (SD) | 83.7 (21.5) |
| eGFR (mL/min/1.73m2)* | |
| n | 127 |
| Mean (SD) | 32.1 (12.2) |
| Hb (g/dL) | |
| n | 128 |
| Mean (SD) | 10.0 (0.6) |
| TSAT (%) | |
| n | 128 |
| Mean (SD) | 23.6 (6.4) |
| Primary cause of CKD, n (%) | |
| Diabetes | 66 (52) |
| Hypertension | 37 (29) |
| Glomerulonephritis | 2 (2) |
| Polycystic kidney disease | 2 (2) |
| Other | 19 (15) |
| Unknown | 2 (2) |
| Time since the onset of CKD, months | |
| Mean (SD) | 29.2 (40.1) |
Measurements must have been made during the 14 days immediately before enrollment to be included
Achievement and maintenance of target Hb level
The target Hb level was achieved by 92% (95% CI: 86%, 96%) of subjects who received at least one dose of darbepoetin alfa, and 97% (95% CI: 93%, 99%) of subjects who completed the study (Table 3).
Table 3.
Hemoglobin results
| N = 128 | |
|---|---|
| Subjects who received at least one dose of darbepoetin alfa, n | 128 |
| Subjects who achieved Hb ≥ 11 g/dL | 118 |
| Proportion (95% CI) | 92% (86%, 96%) |
| Subjects who completed the study, n | 115 |
| Subjects who achieved Hb ≥ 11 g/dL | 112 |
| Proportion (95% CI) | 97% (93%, 99%) |
| Time to achieve a Hb ≥ 11 g/dL, weeks | |
| Median (Q1, Q3) | 5 (3, 8) |
The median (Q1, Q3) time to achieve a Hb ≥ 11 g/dL was 5 (3, 8) weeks. Mean (SD) Hb levels increased steadily during the first 14 weeks, from a baseline of 10.0 (0.6) g/dL to 12.5 (1.2) g/dL, and remained stable for the remainder of the study (Figure 2). In the first 4 weeks of therapy, Hb levels increased by a mean (SD) of 1.0 (0.8) g/dL.
Figure 2.
Mean (SD) Hb level over time
A total of 57 (45%) and 28 (22%) subjects had at least one Hb measurement of > 13.0 g/dL or at least one Hb measurement > 14 g/dL, respectively, at any time during the study. For subjects who had a Hb > 13.0 g/dL or Hb > 14 g/dL, the median (Q1, Q3) time for Hb levels to return to ≤ 13 g/dL were 6 (2, 10) and 8 (5, 8) weeks, respectively.
Darbepoetin alfa dose levels
The median (Q1, Q3) starting Q2W darbepoetin alfa dose was 60.0 (50.0, 80.0) µg, and the median last dose on study (week 19) was 65.0 (30.0, 100.0) µg (Figure 3). The median (Q1, Q3) Q2W dose was 80.0 (60.0, 100.0) µg at the time of achieving the primary Hb endpoint (Hb ≥ 11.0 g/dL) and 64.0 (47.0, 95.0) µg over the course of the study.
Figure 3.
Darbepoetin alfa dose across dosing time points
Iron parameters and RBC transfusions
Nine (7%) subjects received intravenous iron and 78 (61%) subjects received oral iron during the study. Mean (SD) TSAT levels at baseline, weeks 7 and 21 were 23.6 (6.4)%, 19.6 (6.4)%, and 27.3 (13.8)%, respectively. Mean TSAT level was ≥ 20% throughout the course of the study, which is the minimum level recommended in the NKF-K/DOQI guidelines to achieve and maintain a Hb level of 11–12 g/dL with ESA treatment29. Six subjects (5%) received one RBC transfusion and only one subject received ≥ 3 RBC transfusions.
Adverse events
Safety was assessed for subjects who received at least one dose of darbepoetin alfa. AEs reported irrespective of relationship to study treatment were mostly mild to moderate in severity and typical of the CKD nondialysis population (Table 4).
Table 4.
Adverse events
| N = 128 | |
|---|---|
| All AEs, n (%) | 97 (76) |
| Life-threatening AEs | 1 (1) |
| Serious AEs | 26 (20) |
| Treatment-related AEs*, n (%) | 11 (9) |
| Life-threatening treatment-related AEs | 0 (0) |
| Serious treatment-related AEs | 0 (0) |
| AEs leading to withdrawal, n (%) | 3 (2) |
| Death on study†,‡, n (%) | 4 (3) |
| AEs with ≥ 5% occurrence, n (%) | |
| Peripheral edema | 11 (9) |
| Headache | 10 (8) |
| Diarrhea | 9 (7) |
| Hypertension | 9 (7) |
| Arthralgia | 7 (5) |
| Asthenia | 7 (5) |
| Fatigue | 7 (5) |
| Nausea | 7 (5) |
| Urinary tract infection | 7 (5) |
| Vomiting | 7 (5) |
| Back pain | 6 (5) |
| Depression | 6 (5) |
| Hypotension | 6 (5) |
Treatment relatedness was as determined by each study site investigator
Includes deaths occurring within 30 days of last dose of darbepoetin alfa
Deaths were not considered treatment-related by investigators
One or more AEs were reported in 97 (76%) subjects. The most common AEs were peripheral edema (9%), headache (8%), diarrhea (7%), and hypertension (7%). Treatment-related AEs (as determined by each study site investigator) were reported for 11 subjects (9%), but none was considered by the study investigators to be serious or life-threatening. Nontreatment-related serious AEs were reported for 26 subjects (20%). Of special interest, hypertension (worsening or exacerbated hypertension) was reported in 9 (7%) subjects. In each case, the local principal investigator judged the event as not treatment related. Three subjects (2%) discontinued the study because of AEs; one with hyperglycemia, one with cerebrovascular accident, and one with hypertension. Four subjects (3%) died during the study; two due to myocardial infarction (one death occurred within 30 days of the last dose of darbepoetin alfa), one due to acute renal failure, and one had an unspecified cause of death. None of the events leading to discontinuation or death were considered to be treatment related.
Exploratory analysis of subjects who had at least one Hb measurement of > 13 g/dL or one Hb measurement of > 14 g/dL indicated that 41 (72%) and 19 (68%), respectively, reported at least one AE (Table 5). In general, the types and frequency of AEs in these subjects were similar to the AEs in subjects who never had a Hb measurement > 13 g/dL or > 14 g/dL.
Table 5.
Adverse events in subjects with hemoglobin level > 13.0 g/dL or > 14 g/dL
| Subjects with | ||||
|---|---|---|---|---|
| At least one Hb > 13 g/dL (n = 57) |
All Hb ≤ 13 g/dL (n = 71) |
At least one Hb > 14 g/dL (n = 28) |
All Hb ≤ 14 g/dL (n = 100) |
|
| All AEs, n (%) | 41 (72) | 56 (79) | 19 (68) | 78 (78) |
| Serious AEs | 8 (14) | 18 (25) | 3 (11) | 23 (23) |
| Treatment-related AEs* | 7 (12) | 4 (6) | 5 (18) | 6 (6) |
| Treatment-related serious AEs* | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| AEs leading to withdrawal | 2 (4) | 1 (1) | 1 (4) | 2 (2) |
| Deaths on study | 1 (2) | 3 (4) | 0 (0) | 4 (4) |
AEs related to treatment are attributed at the discretion of the investigator administering the treatment
There were no clinically relevant changes in mean laboratory values (hematology and serum chemistry) or mean vital signs (blood pressure) over the course of the study. All bioassay tests for neutralizing antibodies to darbepoetin alfa were negative.
Discussion
The results of this multicenter study indicate that 92% of subjects who received at least one dose of darbepoetin alfa and 97% of subjects who completed the study achieved a Hb level of ≥ 11 g/dL in a median time frame of 5 weeks. These results further confirm the observations made in previous studies demonstrating that Hb levels can be corrected and maintained in ESA-naïve patients who are treated with darbepoetin alfa on a Q2W schedule23–25. Suranyi et al.24 and Toto et al.25 reported that of the subjects who completed the respective studies, 97% and 96%, respectively, achieved the primary efficacy endpoint (Hb level of 11.0–13.0 g/dL for Suryani et al. and ≥ 11.0 g/dL for Toto et al.).
Subjects in this study were successfully initiated on Q2W dosing at 0.75 µg/kg similar to what has been shown in the two de novo Q2W darbepoetin alfa studies mentioned24,25. The median time to response reported here was also consistent with that reported in Suranyi et al.24. However, in this study, the median and the mean darbepoetin alfa doses (80.0 µg and 84.2 µg Q2W, respectively) at time of response were higher than those reported in Suranyi et al. (median Q2W dose of 60 µg to achieve a hemoglobin response of 11.0–13.0 g/dL) and Toto et al. (mean Q2W dose of 63.6 µg at the time the Hb level was ≥ 11 g/dL). Some differences exist between these studies including mean weight (73.8 kg in Suranyi et al., 81.0 kg in Toto et al., and 83.7 kg for the present study), mean baseline TSAT levels (mean [SD] 31.4 [2.2]% for Suranyi et al, 28.0 [21.2]% for Toto et al, and 23.6 [6.4]% for the present study), and dosing rules (dose increase or decrease was based on two consecutive Hb values in both Suranyi et al. and Toto et al., but was based on the most recent Hb measurement in the current study). The differences in dose may be as a result of one or a combination of these differences. Subjects with higher TSAT levels may respond to lower doses of darbepoetin alfa. While these studies were not designed to test that observation, this would be consistent with NKF-K/DOQI guidelines.
The results of this study indicate that darbepoetin alfa was well-tolerated with an AE profile consistent with previous studies23–25; the most common AEs were peripheral edema, headache, diarrhea, and hypertension. None of the serious, fatal, or life-threatening AEs reported in this study were considered related to darbepoetin alfa treatment as determined by the investigator.
In this study, subjects were treated to maintain their Hb levels between 11.0 and 13.0 g/dL and treatment adjustments were made when Hb levels were < 11.0 or > 13.0 g/dL (treatment was withheld only if Hb was > 14.0 g/dL). The results indicate that 45% and 22% of subjects had at least one Hb measurement of > 13 g/dL or one Hb measurement > 14 g/dL, respectively, during the study. Further exploratory analysis summarizing the AEs in subjects with Hb > 13 g/dL or > 14 g/dL indicate that the AEs were similar in incidence and severity to subjects who achieved Hb < 13 g/dL. These results must be interpreted with caution, however, since the study was not designed to assess Hb variability or the outcomes associated with a Hb level outside the range specified by the study. The results are based on post-hoc analyses on a small patient population so their interpretation is limited.
The results of two recent clinical trials, CREATE13 and CHOIR14, demonstrate the need to approach anemia management with care; however, there is considerable evidence supporting the benefits of anemia correction with ESAs when used according to the label in CKD patients15–22. Benefits demonstrated when treating CKD patients with ESAs according to the label guidelines have included slowing the progression of CKD15,16, improving quality-of-life measures17–20, and improving cardiac performance 21,22. Despite this, studies indicate that anemia in the CKD population is not commonly treated in accordance with current guidelines30,31. The United States Renal Data System reports that 45% of incident end-stage renal disease (ESRD) patients start dialysis with a Hb level less than 10 g/dL30. Initiating and maintaining Hb levels with less frequent dosing, such as using Q2W darbepoetin alfa, may offer a more convenient dosing schedule for physicians and patients and provide opportunities for improving anemia management in CKD patients not receiving dialysis.
Other limitations of this study and the results must be acknowledged. These include limitations inherent to open-label, single-arm studies where no comparison is made to a control group. Also, race assignment in this study was mutually exclusive. The lack of multiple race information for subjects who could be identified with more than one race is a study limitation. Additionally, this study assessed efficacy over a 6-month period only, which is a short time period considering that CKD is a chronic disease. A study designed to examine long-term efficacy and safety outcomes of Q2W darbepoetin alfa administered to patients previously naïve to ESA treatment might support the observations seen in this study.
Conclusion
This study demonstrates that ESA-naïve CKD subjects (not receiving dialysis) who received Q2W darbepoetin alfa successfully achieved and maintained target Hb levels, confirming previous findings of de novo Q2W darbepoetin alfa treatment. Furthermore, the safety profile of this study did not suggest safety concerns specifically associated with de novo Q2W darbepoetin alfa in CKD patients who were not receiving dialysis. Initiating anemia treatment and maintaining Hb levels with less dosing frequency (i.e., Q2W administration of darbepoetin alfa) as shown here, provides an added option for patient convenience.
Acknowledgments
Declaration of interest: This study (Aranesp 20030237) was supported by Amgen Inc., Thousand Oaks, CA, USA. M. R. S. has received consultation fees from Amgen Inc and Shire Pharmaceuticals, and speaker honoraria from Amgen Inc. R. G. serves on the Speaker’s Bureau for Amgen Inc and Watson Pharmaceuticals. C. Y. C., R. K., and C. S-B. are employees of Amgen Inc. Some patients for this study were enrolled through the Veterans Administration Medical Center (Salem VA Medical Center, Salem, VA, USA and John D. Dingell VA Medical Center, Detroit, MI, USA). For M.R.S., this clinical trial was conducted through the General Clinical Research Center supported by the National Center for Research Resources, a component of the National Institutes of Health (Grant Number M01 RR000080). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of the NCRR or NIH. The authors acknowledge Yeshi Mikyas, PhD, Amgen Inc., and Mandy Wyles, on behalf of Amgen Inc., for assistance in writing this manuscript. Trial registration of the 20030237 protocol: http://www.clinicaltrials.gov/ct2/show/NCT00112008?term=20030237&rank=1
Footnotes
The data in this paper were previously presented as the abstract, Silver MR, Agarwal AK, Walczyk MH, et al. Every-other-week (Q2W) Aranesp® (Darbepoetin alfa) dosing in patients with chronic kidney disease (CKD) not receiving dialysis. The American Society of Nephrology Renal Week 2005. November 8–13, 2005, Philadelphia, PA, USA
Aranesp, Amgen Inc., Thousand Oaks, CA, USA
The following investigators (listed alphabetically) enrolled patients for this study:
Abu-Hamdan D, Detroit, MI; Agarwal AK, Columbus OH; Albarracin C, Corpus Christi, TX; Anger M, Thornton, CO; Cheriyan R, Fairfax, VA; Coplin RE, Birmingham, AL; Dewberry FL, Clearwater, FL; Dy G, Mansfield, PA; Fadda G, San Diego, CA; Fitz-Patrick D, Honolulu, HI; Flick R, Mesa, AZ; Geronemus R, Lauderdale Lakes, FL; Hamilton M, Ft. Lauderdale, FL; Handelsman S, Atlanta, GA; Hertel J, Augusta, GA; Hura C, San Antonio, TX; Iranmanesh A, Salem, VA; Jackson TL, Beaver, PA; Jones ER, Philadelphia, PA; Kapatkin K, Brandon, FL; Kipnes MS, San Antonio, TX; Kopyt N, Allentown, PA; Krause M, Little Rock, AR; Leiserowitz M, Las Vegas, NV; Liljenquist J, Idaho Falls, ID; Ling BN, Asheville, NC; Mayeda SO, Orange, CA; Navarro JO, Tampa, FL; Ogundipe A, Marietta, GA; Pride ET, North Charleston, SC; Reed JE, Columbus, MS; Silver MR, Cleveland, OH; Walczyk M, Protland, OR; Weinberg MS, Providence, RI; Weissman PN, Miami, FL; Zeig S, Pembroke Pines, FL.
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